Journal of Neurology

, Volume 266, Issue 3, pp 735–744 | Cite as

Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants

  • Anders ToftEmail author
  • Steffen Birk
  • Martin Ballegaard
  • Morten Dunø
  • Lena E. Hjermind
  • Jørgen E. Nielsen
  • Kirsten Svenstrup
Original Communication


SPG31 is a hereditary spastic paraplegia (HSP) caused by pathogenic variants in the REEP1 gene. The phenotype (SPG31) has occasionally been described with peripheral nervous system involvement, in additional to the gradually progressing lower limb spasticity that characterizes HSP. The objective of this study was to characterize patients with pathogenic REEP1 variants and neurophysiologically assess the extent of peripheral nerve involvement in this patient group. Thirty-eight index cases were molecular-genetically tested, yielding two previously reported pathogenic REEP1 variants and a novel missense variant, in a total of four index patients. Three of four probands and five additional family members underwent nerve conduction studies, electromyography, quantitative sensory testing, and examination of the autonomic nervous system. None of the examined patients had completely unremarkable results of peripheral nerve studies. Most showed electrophysiological signs of carpal tunnel syndrome, and one patient demonstrated a multifocal compression neuropathy. Autonomic testing revealed no severe dysfunction, and findings were limited to adrenergic function. HSP caused by pathogenic REEP1 variants may be accompanied by a generally mild and subclinical polyneuropathy with a predisposition to compression neuropathy, and should be considered in such cases.


Hereditary spastic paraplegia REEP1 SPG31 Nerve conduction studies Polyneuropathy Carpal tunnel syndrome 



The study was supported by Ludvig and Sara Elsass Foundation and the Novo Nordisk Foundation.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no competing interests.

Supplementary material

415_2019_9196_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 KB)
415_2019_9196_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 16 KB)


  1. 1.
    Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 21(8334):1151–1155 1(CrossRefGoogle Scholar
  2. 2.
    Zhao X, Alvarado D, Rainier S, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink JK (2001) kal Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet 29(3):326–331CrossRefGoogle Scholar
  3. 3.
    Züchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, Vance JM, Ashley-Koch AE, Pericak-Vance MA (2006) Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 79(2):365–369CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Beetz C, Schüle R, Deconinck T et al (2008) REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 131:1078–1086CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Schlang KJ, Arning L, Epplen JT (2008) Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). BMC Med Genet 9:71CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Hewamadduma C, McDermott C, Kirby J, Grierson A, Panayi M, Dalton A, Rajabally Y, Shaw P (2009) New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics 10(2):105–110CrossRefGoogle Scholar
  7. 7.
    Goizet C, Depienne C, Benard G (2011) REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Hum Mutat 32(10):1118–1127CrossRefGoogle Scholar
  8. 8.
    Horowitz SH, Krarup C (1992) Conduction studies of the normal sural nerve. Muscle Nerve 15(3):374–383CrossRefGoogle Scholar
  9. 9.
    Rosenfalck P, Rosenfalck A (1975) Electromyography—sensory and motor conduction. Findings in normal subjects. Publications from the Laboratory of Clinical Neurophysiology, CopenhagenGoogle Scholar
  10. 10.
    Goldberg JM, Lindblom U (1979) Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J Neurol Neurosurg Psychiatry 42(9):793–803CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Yarnitsky D, Sprecher E (1994) Thermal testing: normative data and repeatability for various test algorithms. J Neurol Sci 125(1):39–45CrossRefGoogle Scholar
  12. 12.
    Low PA, Denq JC, Opfer-Gehrking TL, Dyck PJ, O’Brien PC, Slezak JM (1997) Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve 20(12):1561–1568CrossRefGoogle Scholar
  13. 13.
    Novak P (2011) Quantitative autonomic testing. J Vis Exp 19(53):2502Google Scholar
  14. 14.
    Sletten D, Grandinetti A, Weigand S et al (2015) Normative values for sudomotor axon reflex testing using QSWEAT™. Neurology 84(14 Suppl.):P1.282Google Scholar
  15. 15.
    Low PA (1993) Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin Proc 68(8):748–752CrossRefGoogle Scholar
  16. 16.
    Lipp A, Sandroni P, Ahlskog JE et al (2009) Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch Neurol 66(6):742–750CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Argyriou AA, Karanasios P, Makridou A, Makris N (2009) The significance of second lumbrical-interosseous latency comparison in the diagnosis of carpal tunnel syndrome. Acta Neurol Scand 120(3):198–203CrossRefGoogle Scholar
  18. 18.
    Campbell WW, Carroll DJ, Greenberg MK et al (1999) Practice parameter for electrodiagnostic studies in ulnar neuropathy at the elbow: American Academy of Electrodiagnostic Medicine, American Academy of Neurology, American Academy of Physical Medicine and Rehabilitation. Muscle Nerve 22(suppl 8):S171–205Google Scholar
  19. 19.
    England JD, Gronseth GS, Franklin G (2005) Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 64(2):199–207CrossRefGoogle Scholar
  20. 20.
    Beetz C, Pieber TR, Hertel N (2012) Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am J Hum Genet 91(1):139–145CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Bock AS, Günther S, Mohr J, Goldberg LV, Jahic A, Klisch C, Hübner CA, Biskup S, Beetz C (2018) A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3′UTR-encoded, aggregation-inducing motif. Hum Mutat 39(2):193–196CrossRefGoogle Scholar
  22. 22.
    Høyer H, Braathen GJ, Busk ØL, Holla ØL, Svendsen M, Hilmarsen HT, Strand L, Skjelbred CF, Russell MB (2014) Genetic diagnosis of Charcot–Marie–Tooth disease in a population by next-generation sequencing. Biomed Res Int 2014:210401CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Schottmann G, Seelow D, Seifert F, Morales-Gonzalez S, Gill E, von Au K, von Moers A, Stenzel W, Schuelke M (2015) Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy. Neurol Genet 1(4):e32CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Park HJ, Lee MJ, Lee JE, Park KD, Choi YC (2018) Pathogenic variant of REEP1 in a Korean family with autosomal-dominant hereditary spastic paraplegia. J Clin Neurol 14(2):248–250CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurology, Rigshospitalet, Neuromuscular Research CenterUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of Clinical Neurophysiology, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Clinical Genetics, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
  4. 4.Department of Neurology, Neurogenetics Clinic, Rigshospitalet, Danish Dementia Research CentreUniversity of CopenhagenCopenhagenDenmark
  5. 5.Department of Neurology, Bispebjerg HospitalUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations